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Enhancer Rnas Are an Important Regulatory Layer of the Epigenome

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Enhancer Rnas Are an Important Regulatory Layer of the Epigenome REVIEW ARTICLE https://doi.org/10.1038/s41594-020-0446-0 Enhancer RNAs are an important regulatory layer of the epigenome Vittorio Sartorelli 1 and Shannon M. Lauberth 2 ✉ Noncoding RNAs (ncRNAs) direct a remarkable number of diverse functions in development and disease through their regula- tion of transcription, RNA processing and translation. Leading the charge in the RNA revolution is a class of ncRNAs that are synthesized at active enhancers, called enhancer RNAs (eRNAs). Here, we review recent insights into the biogenesis of eRNAs and the mechanisms underlying their multifaceted functions and consider how these findings could inform future investigations into enhancer transcription and eRNA function. he explosion of high-throughput sequencing data has Many different models for how enhancers function in gene con- revealed the complexity and diversity of the transcriptome. trol have been proposed since their initial discovery nearly four TThese data have also unexpectedly revealed that only 1–2% decades ago19–21. Specifically, there is considerable evidence demon- of the transcriptome provides instructions for the synthesis of strating that looping of distal enhancers to their target promoters is functional proteins, while the remaining 98–99% gives rise to a required for enhancer function (reviewed in ref. 22). For example, plethora of ncRNAs, including transfer RNAs (tRNAs), ribosomal a key study revealed that experimental induction of chromatin RNAs (rRNAs), intronic RNAs, small nuclear (sn)RNAs, small looping between the mouse β-globin (Hbb) promoter and its asso- nucleolar (sno)RNAs, microRNAs (miRNAs) and long noncoding ciated enhancer region results in transcriptional activation of the RNAs (lncRNAs). A recent addition to the expanding list of regu- Hbb gene23. Additional analyses of the forced looping of the Hbb latory ncRNAs is the emerging class of enhancer RNAs (eRNAs), enhancer and promoter regions revealed that enhancer–promoter which are transcribed from enhancers in a tissue-specific man- contacts affect transcription by supporting an increase in the tran- ner. Increasing evidence that ncRNAs regulate gene expression scriptional burst fraction (number of transcribing alleles), although has fundamentally altered how the scientific community views the burst size (number of transcripts produced) was unaltered24. RNA-mediated gene regulation. These new advances in our under- The role of looping in the activation or increased rate of transcrip- standing of ncRNAs have also piqued an interest in pursuing inves- tion may be due to the binding of transcription factors, cofactors tigations of them, as the functions of the vast majority of ncRNAs and the general transcription machinery to enhancers, raising the remain to be determined. local abundance of the transcription machinery within the vicin- Enhancers are classically defined as DNA sequences that regulate ity of specific target genes. Enhancer looping has also been shown the gene expression networks underlying distinct cellular identi- to play a role in RNA polymerase II (RNAPII)-mediated transcrip- ties and cellular responses to environmental cues1–7. The ENCODE tional elongation. Specifically, the LIM domain–binding protein 1 Consortium estimates that there are >400,000 putative enhancers (LDB1), which establishes promoter–enhancer looping, plays a key encoded by the human genome8. Taken together, the evidence that role in regulating the pause release of RNAPII within the β-globin enhancers account for a significant proportion of the genome and the gene25,26. Enhancers may also regulate target genes via transcripts identification of disease-associated genetic variants within enhancers produced from the enhancer regions themselves. eRNA produc- underscores the importance of understanding how these elements are tion is a widespread phenomenon that has been implicated in the regulated and how they function in gene expression control8,9. While regulation of gene expression in multiple cell types in response to sequencing technologies have advanced the ability to predict enhancer various stimuli7,27–32. The emerging prevalence of noncoding eRNAs location and activity, their functional dissection remains challenging makes them well positioned to dynamically remodel cellular tran- due, in part, to their ability to act over long and variable distances scriptomes and adds a new layer of complexity to gene regulation. with respect to their target genes and to the propensity of individual However, an issue that remains to be resolved is whether eRNAs enhancers to regulate multiple genes (reviewed in ref. 10). Additional have direct roles in gene control, as current efforts to determine challenges are that enhancer activity is dynamic and restricted to par- this face the challenge of uncoupling eRNA function from the act ticular cell types or tissues and environmental signals3–7. Moreover, the of enhancer transcription. Thus, it remains necessary to develop prediction of specific sequences that contribute to enhancer function tools to experimentally manipulate and model the direct functions is problematic because of their modest sequence conservation across of eRNAs. species11–15. It may be that a common function underlies enhancer evolution, given that enhancer function has been shown to be con- Enhancers as functional noncoding RNA transcription units served without discernible sequence conservation16–18. Together, these Nearly a decade ago, two studies reported the intriguing finding that studies indicate the need to continue improving methodologies that enhancer regions support transcription and give rise to noncoding aid in both the functional dissection of enhancers and in uncovering eRNAs33,34. Since the discovery of eRNAs, there have been numerous the mechanisms directing their evolution. reports that eRNA is synthesized in a cell-type and signal-dependent 1Laboratory of Muscle Stem Cells & Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA. 2Section of Molecular Biology, University of California, San Diego, La Jolla, CA, USA. ✉e-mail: [email protected] NATURE STRUCTURAL & MOLECULAR BIOLOGY | www.nature.com/nsmb REVIEW ARTICLE NATURE STRUCTURAL & MOLECULAR BIOLOGY manner3–7. Because eRNAs are not readily detectable in steady-state transcript, S2P levels increase and S5P levels decrease69–71. On the RNA-sequencing data, their annotation depends on sequencing other hand, the elongation of enhancer transcripts is distinguished nascent RNA using approaches that include global run-on sequenc- by low levels of the S2P form of RNAPII and minimal levels of the ing (GRO-seq)3,5–7,27,35–40, precision run-on nuclear sequencing elongation-specific histone mark H3K36me3, both of which are (PRO-seq)41 and cap analysis gene expression (CAGE)42,43. These enriched within gene bodies of lncRNAs and mRNAs55,72. Low lev- nascent transcription assays have been instrumental in uncovering els of S2P are consistent with the enrichment of the Tyr1P form of a wide array of ncRNAs, including long noncoding RNAs, enhancer RNAPII that is specifically found at active enhancers and not at RNAs, promoter upstream transcripts and upstream antisense the sense strand of gene promoters73,74. The prevalence of Tyr1P RNAs. Indeed, global annotation analyses have revealed that eRNA coincides with the production of eRNAs and promoter-directed transcripts account for a large proportion of initiation events in the upstream antisense transcripts (PROMPTs), both of which are rela- transcriptome, with approximately 40,000–65,000 eRNAs expressed tively unstable due to exosome-mediated degradation73. Notably, in human cells4,44. The annotation of such transcripts in Drosophila Tyr1P is required for transcription termination control in yeast68,75 melanogaster45,46 and Caenorhabditis elegans47 reinforces the finding and, more recently, has been shown to prevent transcription that eRNAs are a common feature of active enhancers in metazoans. readthrough at mammalian gene ends76. However, no apparent con- eRNAs are produced from active enhancers that share several tribution of Tyr1P to the regulation of transcription readthrough is features: (i) an open chromatin state, reflected by the presence of observed at enhancers76. Thus, Tyr1P accumulation may contribute DNase hypersensitive sites (DHSs); (ii) binding of transcription to different functional consequences at promoters and enhancers. factors and cofactors, including the histone acetyltransferase p300 Further demonstrating a role for elongation in enhancer regula- and cAMP response element–binding protein (CBP); and (iii) the tion, the RNAPII-associated transcription elongation factor SPT6 co-occurrence of histone H3 lysine 4 monomethylation (H3K4me1) contributes to the recruitment of Integrator to lncRNA genes. The and histone H3 lysine 27 acetylation (H3K27ac)48–52. While these Integrator subunit INTS3 is enriched at enhancer regions that gener- features have guided enhancer identification, not all active enhanc- ate bidirectional eRNAs, and SPT6 depletion substantially decreases ers that share these features direct eRNA production53. Also, not INTS3 recruitment and eRNA production77,78. The elongation factor all active enhancers support comparable levels of transcriptional ELL3 has also been shown to regulate occupation of enhancers by activity. Higher levels of eRNA synthesis have been shown to cor- RNAPII79. Additional studies are needed to determine whether dis- relate with
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